This proposal is based on an analysis of serum from melanoma patients treated with the PD-1 antibody nivolumab (NIVO) showing that high levels of IL-6 and acute phase reactants (APP) induced by IL-6 like C- reactive protein (CRP) are associated with poor survival. We hypothesize that CRP and other APP induced by IL-6 are associated with resistance to checkpoint inhibition in melanoma, and are immunosuppressive. This is supported by our preliminary data showing that CRP levels are associated with low response rates and short survival with NIVO or ipilimumab (IPI). IL-6 promotes the synthesis of CRP and other APPs from the liver, and its levels are also associated with low response rates, short survival and therapeutic resistance in patients receiving NIVO, IPI or combination immune checkpoint blockade (ICB). Patients with low IL-6 at baseline or after treatment with ICB have high response rates and long survivals. To overcome the immune suppression observed with CRP and reverse ICB resistance associated with high IL-6, we will add the IL-6 receptor blocking antibody tocilizumab to IPI and NIVO in patients with metastatic melanoma. Our overarching hypothesis is that levels of IL-6 and CRP in baseline serum and other biomarkers in serum, PBMCs and tumor will predict efficacy and toxicity in a phase II trial of IPI/NIVO with tocilizumab and that IL-6 blockade will augment the efficacy of, and reduce toxicity from combined ICB. These biomarkers will provide insight into host/tumor mediators of ICB and help direct patients to the most effective immunotherapy based on their baseline and on-treatment levels of IL-6/CRP and other biomarkers. Co-primary endpoints of the trial include best overall response rate and toxicity since IL-6 blockade has also been shown to reduce immune-related adverse events with immunotherapy. A Simon two-stage design trial will include 67 patients that will receive the triple combination and will be supported by BMS. In this proposal, we wish to support the correlative marker studies based on that phase II trial. Analyses of the serum, tumor and peripheral blood will be carried out to establish biomarkers of efficacy and toxicity and help understand the basis for resistance to combination ICB in melanoma based on three specific aims: 1. To determine if baseline levels, or on-treatment changes in a serum mass spectrometry-MALDI-TOF protein signature and acute phase reactants and cytokines are associated with response and toxicity in a phase II trial of IPI/NIVO with the IL-6 receptor blocking antibody tocilizumab; 2. To determine if baseline or on-treatment changes in peripheral blood and tumor T cell phenotype and function assessed by multi-parameter flow cytometry, Ab-Seq and IsoLight assays, peripheral blood dendritic cell phenotype and function and tumor class I and II expression, PD-L1 levels and RNA seq signatures are associated with response and toxicity in a phase II study of IPI/NIVO with tocilizumab; and 3. To integrate the serum, peripheral blood and tumor biomarkers of aims 1 and 2 to assess if a consolidated signature is associated with response and toxicity in a phase II study of IPI/NIVO with tocilizumab.